Lewis Acid-Catalyzed Additions of (Benzotriazol-1-yl)diethoxymethane

Addition of (benzotriazol-1-yl)diethoxymethane 11 to various acyclic and cyclic enol ethers and enamides produces the corresponding adducts, which wer...
0 downloads 0 Views 277KB Size
Download PDF
700

J. Org. Chem. 1997, 62, 700-705

Lewis Acid-Catalyzed Additions of (Benzotriazol-1-yl)diethoxymethane to Enol Ethers and Enamides. New Syntheses of β-Alkoxyalkanal and β-Aminoalkanal Acetals Alan R. Katritzky,* Sergei A. Belyakov, Bogumila Rachwal, and Jean-Luc Moutou Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200 Received July 1, 1996X

Addition of (benzotriazol-1-yl)diethoxymethane 11 to various acyclic and cyclic enol ethers and enamides produces the corresponding adducts, which were reacted with either NaAlH4 or Grignard reagents to afford acyclic acetal-ethers (18a-f), cyclic R-(substituted)-β-acetals (19a-c), aminoacetals (24a,b), and 1,3-amino-ethers (25), all known but previously difficult-to-access classes of compounds. Introduction Recent reports from our laboratory have described the additions of 1-(R-alkoxybenzyl)benzotriazoles to enol ethers which opened a new route to 1,3-diethers (Scheme 1),1 of 1-(R-aminoalkyl)benzotriazoles to enol ethers leading to 1,3-amino-ethers,2 and of 1-(R-aminoalkyl)benzotriazoles to N-vinyl amides to give unsymmetrically substituted 1,3-diamines (Scheme 2).3,4 The benzotriazole-containing starting materials 1 and 5 (Schemes 1, 2) can be considered as protected oxonium (2) or immonium (6) cations because of the easy heterolysis of the C-Bt bond under mild acidic catalysis (p-toluenesulfonic acid) and consequently react with enol ethers and enamides to form the corresponding benzotriazolyl-substituted addition products (c.f. 3, 7, 9). Replacement of the benzotriazole moiety in 3, 7, 9 then gives the final 1,3diethers, 1,3-amino-ethers, or 1,3-diamines (c.f. 4, 8, 10). We have now investigated similar Lewis acid-catalyzed additions of (benzotriazol-1-yl)diethoxymethane to enol ethers and enamides and have shown that the benzotriazole-substituted acetals thus obtained undergo further transformations (Grignard reaction, reduction, followed by another Grignard reaction, etc.) to provide direct and efficient routes to a wide range of β-alkoxy- and β-aminoalkanal acetals, and 1,3-amino-ethers. (Benzotriazol-1-yl)diethoxymethane 11 (Scheme 3) was readily prepared in good yield as a stable (shelf life more than 8 months), colorless, viscous liquid by the reaction of benzotriazole with ethyl orthoformate. The crude product 11 usually contains ca. 5-10% of 1-ethylbenzotriazole as a byproduct, which can be removed by distillation; however, this byproduct does not affect the further reactions of 11, and we therefore used crude 11 in subsequent transformations. Reactions with Enol Ethers. Acetal 11 reacted with enol ethers 12a-c under catalysis by boron trifluoride, p-toluenesulfonic acid, or zinc bromide to give the addition compounds 13a-c. These acid catalysts all work well for each vinyl substrate. Data in the Experimental Abstract published in Advance ACS Abstracts, January 15, 1997. (1) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel, P. J. J. Org. Chem. 1992, 57, 4925. (2) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel, P. J. J. Org. Chem. 1992, 57, 4932. (3) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem. 1993, 58, 812. (4) Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Org. Chem. 1994, 59, 5206. X

S0022-3263(96)01233-9 CCC: $14.00

Scheme 1

Scheme 2

Section simply underline the equality of the catalytic effect of such Lewis acids in our reactions. The mechanism of the reaction clearly involves the ionization of 11 followed by stepwise addition of the ion pair thus formed to the double bond of enol ether (Scheme 3). The crude products contained small amounts (5-9%) of ethers 14ac, as shown by NMR spectra.23 The formation of the byproduct ethers 14 is explained by the addition to the double bond of vinyl ether of free benzotriazole which generated by reaction of ethanol with 11, the ethanol being formed by elimination from 13a-c (compare with formation of vinyl ethers from diacetals5,6 ). Compounds 13a-c were separated by column chromatography and were characterized by NMR spectroscopy. However, the presence of small amounts of 14a-c does not affect the (5) Povarov, L. S. Russ. Chem. Rev. (Engl. Transl.) 1965, 34, 639. (6) Mikhailov, B. M.; Povarov, L. S. J. Gen. Chem. USSR (Engl. Transl.) 1959, 29, 2048.

© 1997 American Chemical Society

Syntheses of β-Alkoxyalkanal and β-Aminoalkanal Acetals Scheme 3

J. Org. Chem., Vol. 62, No. 3, 1997 701 Scheme 5

Scheme 6

Scheme 4

course of further chemical transformations of 13a-c, and we therefore normally used the crude products 13a-c for subsequent transformations. Acetal 11 reacts similarly with cyclic enol ethers 15a,b to give 2-(benzotriazolyl)-3-(diethoxymethyl)tetrahydrofuran (16a) and 2-(benzotriazolyl)-3-(diethoxymethyl)tetrahydropyran (16b) in high yields (Scheme 4). The crude products 16a,b also contained compounds 17a,b. We separated one pure stereoisomer of acetal 16b, namely erythro-2-(benzotriazol-1-yl)-3-(diethoxymethyl)tetrahydropyran, to assist with the complete assignment of the NMR signals, since the spectrum of a crude reaction mixture was complex. On the basis of HETCOR results, we assigned doublets at 4.42 and 6.36 ppm in the 1H NMR spectrum of the isolated isomer to the protons at C(2) and at C(3′) positions of the pyran-acetal system. Irradiation of the former proton during NOEDIF experiment caused a ca. 10% resonance enhancement of the C(3′) proton signal, which allowed assignment of the isolated isomer as erythro. The coupling constant of the proton adjacent to the C(3′) atom (acetal proton) is characteristic (ca. 8.0 Hz), which was useful for the assignment of the related compound, 19c (see below). However, for further preparative work, we used the crude product mixtures (16a/17a and 16b/17b) without separation at this stage. Transformations of the β-(Diethoxymethyl)-rbenzotriazolylalkyl Ethers 13 and 16. The acetals 13a-e underwent Grignard reactions with various alkyl-, aryl-, and alkynylmagnesium halides in refluxing toluene with selective replacement of the benzotriazolyl group to give the corresponding substituted acyclic acetal-ethers 18a-f (Scheme 5) and cyclic acetal-ethers 19a-c (Scheme 6). These reactions of the acyclic compounds 13a-c gave crude reaction products containing 70-85% of the desired acetal-ethers 18a-f, according to the NMR data. Pure

acetal-ethers 18a-f were isolated either by column chromatography (18a,b,d-f) or by Kugelrohr distillation (18c). NMR spectra of the compounds 18a-f do not contain signals for a benzotriazolyl substituent, but instead have the appropriate sets of the signals for the corresponding R-substituents. No transformations of the geminal diethoxy functionality with the Grignard reagents were detected in any of these reactions: in the 1 H and 13C NMR spectra of all the acetal-ethers 18a-f the signals for both geminal ethoxy substituents are essentially unchanged from those in 13a-c. Formation of the five-membered cyclic acetal-ethers 19a,b occurred stereoselectively to give only the threoisomers, i.e., the introduction of the bulky phenyl substituent proceeds in the less sterically hindered way. The six-membered cyclic acetal-ether 19c was obtained as a 1:2 mixture of erythro- and threo-isomers, which were separated by column chromatography. Assignment of the 1H NMR signals for both erythro- and threo-19c is hindered by overlapping of the C(3) proton signals with the signals for the one of CH2 groups. Nevertheless, based on the results for compound 16b, the erythroconfiguration was assigned to the specimen of 19c with a 1H NMR doublet located in the same position and with the same coupling constant as 16b. Total yields of the cyclic acetal-ethers were above 80% (based on the NMR of reaction mixtures) for all the compounds 19a-c. Diethyl acetals 18, 19 are unstable compounds and readily decompose during column chromatography. Therefore, isolated yields given for these compounds in the Experimental Section are substantially lower than those estimated from the NMR. However, as shown on the examples of the amino-acetals 24a,b, larger than preparative amounts of such acetals might be successfully purified by distillation.

702 J. Org. Chem., Vol. 62, No. 3, 1997 Scheme 7

Scheme 8

We prepared threo-2-phenyl-1,2,3,4-tetrahydrofuran3-carboxaldehyde 2,4-dinitrophenylhydrazone (20) in 72% yield by reacting the cyclic acetal-ether 19a with 2,4dinitrophenylhydrazine in refluxing acetic acid. Reactions with Enamides. Addition of boron trifluoride etherate to a neat mixture of acetal 11 and enamides 21a or 21b at 20 °C (Scheme 7) produces in high yield the amido-acetals 22a and 22b, respectively, each admixed with the corresponding amide 23a,b (ca. 5-12%), similar to the reactions involving enol ethers. Yields were based on NMR of the crude mixtures. We isolated and characterized the individual amido-acetal 22b as a solid; however, as in the case of ether-acetals 13a-c, we used 22a with its minor impurities of 23a for the further reactions, because reduction of the contaminant 23a gives a volatile product easily removable by distillation or column chromatography. Compound 22a was characterized by the 13C NMR data (see Experimental Section). Reductions of amido-acetals 22a,b with NaAlH4 in THF at 20 °C afforded the corresponding β-amino aldehyde ethyl acetals 24a,b in good yields (82% and 92%, respectively) as a result of reduction of amido group and simultaneous substitution of benzotriazole moiety by a hydrogen atom (Scheme 8). These reactions are vigorous and require external cooling, especially at the beginning. Both 24a and 24b can be purified by column chromatography; however, distillation provides much better yields and comparable purity. Both the 1H and the 13C NMR spectra of β-amino aldehyde ethyl acetals 24a,b contain characteristic sets of signals: in the proton NMR there is a triplet at ca. 4.5-4.6 ppm assigned to the proton of the acetal group, and no signals in the aromatic region of the spectra, thus indicating a complete displacement of the benzotriazolyl moiety by hydrogen. In the carbon NMR there are no signals at low field responsible for the carbon atom of amido group, but instead an extra secondary carbon signal appears at high field (ca. 4060 ppm), corresponding to the carbon atom from the reduced amido group.

Katritzky et al.

Grignard reaction of the acetal 24b with PhMgBr in refluxing toluene after 5 h afforded the corresponding substituted amino-ether 25 in 60% yield. In the 1H NMR spectrum of 25 a new multiplet at ca. 7.27 ppm appeared, and the integration of the signals of ethoxy group was decreased, matching a calculation for three and two protons, respectively, thus confirming the successful displacement of one of the acetal ethoxy groups. Displacement of one of the oxygens (ethoxy group) by carbon (phenyl ring) resulted in the upfield shift of the signal of ethereal R-carbon atom (from 101.6 to 80.4 ppm) in the 13C NMR spectrum of the amino-ether 25. Manipulations with the type of substituents in the starting vinyl amides 21 and in Grignard reagents thus open the possibility to vary substantially the structure of the amino-ethers 25. Comparison with Previous Work. Mayr and coworkers7 synthesized variously substituted propanal dimethyl acetals and investigated systematically the reactions of acetals and ortho esters with vinyl methyl ether, concluding the following order of reactivity: formaldehyde acetals < aliphatic acetals < ortho esters < aromatic acetals ) unsaturated aliphatic acetals. The addition of ortho esters to enol ethers has significant synthetic value since the final 1,1,3,3-tetraalkoxypropanes are malonaldehyde equivalents and are widely used in the heterocyclic chemistry. They are commercially available products but are usually manufactured by other methods (see e.g. lit.8). By contrast, the addition of either acetals or ortho esters to enamides has not been previously studied. An advantage of our new methodology is that the acetals 13 are inactive toward competitive addition to enol ethers: in all the cases we used acetal and vinyl ether in equimolar ratio and did not observe the formation of any secondary addition products, while previously described reactions of stoichiometric amounts of acetals and enol ethers led to the formation of oligomers.5,9 This difference in the reactivity patterns in acetals and 11 becomes crucial as far as their reactions with cyclic enol ethers are concerned. Substituted tetrahydrofurans and tetrahydropyrans are the structural subunits in naturally occurring polyether antibiotics, pheromones, etc.10,11 Additions of acetals to dihydrofurans and dihydropyrans were previously found to yield the corresponding 2-alkoxy3-(R-alkoxy)alkyltetrahydrofurans or -pyrans;5,12,13 however, these reactions are often complicated by the formation of secondary condensation products. 2-Substituted tetrahydrofuran(pyran)-3-carboxaldehydes were previously difficult to access: the most frequently used method for their preparation is a threestep procedure based on (i) the preparations of either 2-(disubstituted)-4,7-dihydro-1,3-dioxepines or 2-(disubstituted)-5,6-dihydro-1,3-dioxocins, (ii) ruthenium hydride-catalyzed isomerization of these cyclic compounds (migration of double bond), and (iii) 1,3-alkyl migration ring construction catalyzed by Lewis acids to give, after hydrolysis of the intermediate acetal, the corresponding aldehydes in ca. 20-30% overall yields.10,11,14,15 (7) von der Bru¨ggen, U.; Lammers, R.; Mayr, H. J. Org. Chem. 1988, 53, 2920. (8) Eckhardt, H.; Halbritter, K.; Rohr, W. Ger. Offen. DE 3,145,709; Chem. Abstr. 1983, 99, 53734. (9) Hoaglin, R. I.; Hirsh, D. H. J. Am. Chem. Soc. 1949, 71, 3468. (10) Frauenrath, H.; Philipps, T. Tetrahedron 1986, 42, 1135. (11) Frauenrath, H.; Sawicki, M. Tetrahedron Lett. 1990, 31, 649. (12) Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. Fr. 1950, 1155. (13) Brannock, K. C. J. Org. Chem. 1959, 24, 1382. (14) Suzuki, H.; Yashima, H.; Hirose, T.; Takahashi, M.; Moro-oka, Y.; Ikawa, T. Tetrahedron Lett. 1980, 21, 4927.

Syntheses of β-Alkoxyalkanal and β-Aminoalkanal Acetals

β-Amino aldehydes are considered to be an important building blocks in the biosynthesis and total synthesis of various alkaloids, i.e., antitumor alkaloids Manzamine A1 and Manzamine D216 and all Elaecarpus alkaloids.17 Most β-amino aldehydes are unstable and spontaneously polymerize.16 Some examples of the Michael addition of acrolein or related compounds to secondary amines which resulted in the preparation of substituted β-amino aldehydes are described in the literature,16 but the stability of these compounds was low and they had to be used immediately after their preparation in solution. More stable acetals of β-amino aldehydes were recently prepared by the reaction of N-alkenyl-N,N-dialkylamines with methanol catalyzed by CuCl2/LiPdCl4 in moderate to good yields.18 We believe that the presently reported preparation of β-amino-acetals holds great promise as precursors of β-amino aldehydes and 1,3-amino-ethers because of the easy manipulation and readily available starting materials. In summary, we found that the addition of (benzotriazol-1-yl)diethoxymethane 11 to various acyclic and cyclic enol ethers and enamides produces the corresponding 1:1 adducts with no further additions observed. These adducts can be easily modified by the reactions with either NaAlH4 or with Grignard reagents, thus yielding several classes of compounds which were previously known but accessible only with difficulty: acyclic acetalethers 18a-f, cyclic R-(substituted)-β-acetals 19a-c, amino-acetals 24, and the corresponding 1,3-aminoethers of type 25.

Experimental Section General. See refs 19, 20. 1H NMR spectra were recorded at 300 MHz, and 13C NMR spectra at 75 MHz in CDCl3. All the compounds containing the benzotriazole moiety which are described in the present paper consist of the mixture of benzotriazol-1-yl (Bt1) and benzotriazol-2-yl (Bt2) isomers in different ratios. Both isomers readily undergo the transformations described here, and therefore their isolation was not performed. Experimental Section contains NMR data of the mixtures of Bt1 and Bt2 isomers, without their complete assignments. (Benzotriazol-1-yl)diethoxymethane (11). A mixture of benzotriazole (5.96 g, 50 mmol) and triethyl orthoformate (7.41 g, 50 mmol) was heated together with perfluorocarbon fluid (3M Co. performance fluid, FC-84;21,22 ) (30 mL) in a roundbottom flask fitted with a reversed Dean-Stark trap. After 20 h of reflux (during this time ethanol was collected in the trap), the mixture was allowed to cool and ethyl acetate (40 mL) was added. The ethyl acetate layer was separated, the solvent was evaporated in vacuo, and the residue was subjected to fractional distillation, collecting the fraction with bp 95-97 °C/0.15-0.20 Torr. Colorless, viscous liquid; yield 86%; 1H NMR δ 1.25 (t, J ) 7.1 Hz, 6H), 3.54 (dq, J ) 9.4 and 7.1 Hz, 2H), 3.80 (dq, J ) 9.4 and 7.1 Hz, 2H), 6.79 (s, 1H), 7.40 (t, J ) 7.9 Hz, 1H), 7.50 (t, J ) 8.1 Hz, 1H), 7.92 (d, J ) 8.3 Hz, 1H), 8.07 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.6, 63.1, 105.9, 112.2, 119.6, 124.4, 127.7, 130.8, 146.4. Anal. Calcd for C11H15N3O2: C, 59.71; H, 6.83. Found: C, 59.36; H, 6.54. (15) Frauenrath, H.; Philipps, T. Liebigs Ann. Chem. 1985, 1951. (16) Chesney, A.; Marko, I. E. Synth. Commun. 1990, 20, 3167. (17) Chen, C.-K.; Hortmann, A. G.; Marzabadi, M. R. J. Am. Chem. Soc. 1988, 110, 4829. (18) Lai, J.-y.; Shi, X.-x.; Dai, L.-x. J. Org. Chem. 1992, 57, 3485. (19) Katritzky, A. R.; Rachwal, B.; Rachwal, S.; Abboud, K. A. J. Org. Chem. 1996, 61, 3117. (20) Katritzky, A. R.; Xie, L. J. Org. Chem. 1995, 60, 3707. (21) Zhu, D.-W. Synthesis 1993, 953. (22) Katritzky, A. R.; Toader, D.; Jiang, J. Org. Prep. Proced. Int. 1995, 27, 179.

J. Org. Chem., Vol. 62, No. 3, 1997 703 General Procedure for the Preparation of 1-(Benzotriazolyl)-1-alkoxy-3,3-diethoxypropanes (13a-c), 2-(Benzotriazolyl)-3-(diethoxymethyl)tetrahydrofuran (16a), and 2-(Benzotriazolyl)-3-(diethoxymethyl)tetrahydropyran (16b). A mixture of acetal 11 (6.75 mmol), alkyl vinyl ether 12a-c or cycloalkyl vinyl ether 15a,b (6.75 mmol), and the corresponding Lewis acid catalyst (see below) was stirred at rt for a time specified (see below). The residue was diluted with diethyl ether, and the organic layer was successively washed with NaOH (1 M solution in water) and then with brine, separated, and dried over anhyd MgSO4. Evaporation of the solvent in vacuo gave acetal 13 or 16 together with small amounts of the ether 14 or 17. NMR assignments below are given only for compounds 13 or 16. 1-(Benzotriazolyl)-1,3,3-triethoxypropane (13a): catalyst: p-TsOH (0.01 g), reaction time: 1 h; oil; yield 85% (based on the NMR); 1H NMR δ 1.11-1.21 (m, 9 H), 2.43 (ddd, J ) 14.0, 6.4 and 6.4 Hz, 1H), 2.63 (ddd, J )13.9, 7.4 and 5.2 Hz, 1H), 3.24-3.35 (m, 1H), 3.40-3.69 (m, 5H), 4.51 (dd, J ) 6.6 and 5.2 Hz, 1H), 6.21 (dd, J ) 7.4 and 6.1 Hz, 1H), 7.40 (t, J ) 8.2 Hz, 1H), 7.49 (t, J ) 8.0 Hz, 1H), 7.77 (d, J ) 8.3 Hz, 1H), 8.08 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.3, 14.9, 38.6, 61.2, 61.5, 64.1, 87.0, 98.9, 110.6, 119.7, 123.8, 127.1, 131.2, 146.3. 1-(Benzotriazolyl)-1-(isobutyloxy)-3,3-diethoxypropane (13b): catalyst: BF3.Et2O (0.03 mL), reaction time: 20 h; oil; yield 88% (based on the NMR); 1H NMR δ 0.80 (d, J ) 6.7 Hz, 3H), 0.84 (d, J ) 6.7 Hz, 3H), 1.16 (t, J ) 7.0 Hz, 3H), 1.19 (t, J ) 7.1 Hz, 3H), 1.81 (sextet, J ) 6.7 Hz, 1H), 2.37 -2.46 (m, 1H), 2.65 (ddd, J ) 14.0, 7.7 and 5.0 Hz, 1H), 2.97 (dd, J ) 8.9 and 6.7 Hz, 1H), 3.25 (dd, J ) 9.0 and 6.4 Hz, 1H), 3.40-3.54 (m, 2H), 3.56-3.70 (m, 2H), 4.55 (dd, J ) 6.7 and 5.1 Hz, 1H), 6.19 (dd, J ) 7.6 Hz and 5.9 Hz, 1H), 7.39 (t, J ) 7.9 Hz, 1H), 7.49 (t, J ) 8.2 Hz, 1H), 7.77 (d, J ) 8.3 Hz, 1H), 8.09 (d, J ) 8.5 Hz, 1H); 13C NMR δ 15.0, 15.1, 18.9, 27.9 (2 C), 38.7, 61.4, 61.5, 75.4, 87.6, 99.0, 110.8, 119.8, 123.9, 127.2, 131.3, 146.4. 1-(Benzotriazolyl)-1-(dodecyloxy)-3,3-diethoxypropane (13c): catalyst: p-TsOH (0.01 g), reaction time: 2 h; oil; yield 87% (based on the NMR); 1H NMR δ 0.80 (t, J ) 6.5 Hz, 3H), 1.08-1.17 (m, 24H), 1.36-1.47 (m, 2H), 2.35 (dt, J ) 14.0 and 6.3 Hz, 1H), 2.56 (ddd, J ) 12.7, 7.6 and 5.2 Hz, 1H), 3.09-3.18 (m, 1H), 3.33-3.45 (m, 3H), 3.50-3.61 (m, 2H), 4.55 (dd, J ) 6.6 and 5.1 Hz, 1H), 6.12 (dd, J ) 7.5 and 6.2 Hz, 1H), 7.31 (t, J ) 7.1 Hz, 1H), 7.41 (t, J ) 7.2 Hz, 1H), 7.69 (d, J ) 8.3 Hz, 1H), 8.00 (d, J ) 8.2 Hz, 1H); 13C NMR δ 14.0, 15.1, 15.2, 22.6, 25.8, 29.1, 29.2 (2 C), 29.4 (2 C), 29.5 (2 C), 31.8, 38.9, 61.5, 61.7, 69.0, 87.6, 99.2, 110.9, 120.0, 124.1, 127.3, 131.5, 146.7. 2-(Benzotriazolyl)-3-(diethoxymethyl)tetrahydrofuran (16a): catalyst: BF3‚Et2O (0.03 mL), reaction time: 1 h; oil; yield 84% (based on the NMR); 1H NMR δ 1.12 (t, J ) 7.1 Hz, 3H), 1.18 (t, J ) 7.1 Hz, 3H), 2.07-2.20 (m, 1H), 2.422.55 (m, 1H), 3.48-3.70 (m, 4H), 3.70-3.82 (m, 1H), 4.024.22 (m, 2H), 4.62 (d, J ) 7.4 Hz, 1H), 6.43 (d, J ) 3.1 Hz, 1H), 7.35-7.40 (m, 1H), 7.47-7.52 (m, 1H), 7.69 (d, J ) 8.3 Hz, 1H), 8.06 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.7, 14.8, 26.9, 47.3, 61.2, 61.9, 68.8, 88.6, 102.3, 109.8, 119.4, 123.7, 127.1, 132.4, 145.8. erythro-2-(Benzotriazol-1-yl)-3-(diethoxymethyl)tetrahydropyran (16b): catalyst: BF3.Et2O (0.03 mL), reaction time: 24 h; oil; yield 82% (based on the NMR); 1H NMR δ 0.64 (t, J ) 7.0 Hz, 3H), 1.22 (t, J ) 7.0 Hz, 3H), 1.80-1.90 (m, 3H), 2.00-2.10 (m, 1H), 2.62-2.76 (m, 3H), 3.42-3.70 (m, 5H), 4.42 (d, J ) 8.0 Hz, 1H), 6.36 (d, J ) 4.2 Hz, 1H), 7.40 (t, J ) 8.2 Hz, 1H), 7.52 (t, J ) 8.3 Hz, 1H), 7.64 (d, J ) 8.4 Hz, 1H), 8.08 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.6, 15.5, 20.9, 24.7, 42.9, 61.8, 63.1 (2C), 81.0, 103.5, 110.3, 119.7, 124.2, 127.5, 133.9, 145.1. General Procedure for the Preparation of 1-(Substituted)-1-alkoxy-3,3-diethoxypropanes (18a-f), 2-(Substituted)-3-(diethoxymethyl)tetrahydrofurans (19a,b), and 2-Methyl-3-(diethoxymethyl)tetrahydropyran (19c). To a refluxing solution of the corresponding diethyl acetal 13a-c or 16a,b (10 mmol) in toluene (50 mL) was added a solution of the corresponding Grignard reagent RMgHlg,

704 J. Org. Chem., Vol. 62, No. 3, 1997 prepared immediately prior to use from the appropriate alkyl, aryl, or arylalkynylhalide (20 mmol) and magnesium turnings (5.34 g, 22 mmol), in ether (50 mL) dropwise at such rate that the ether distilled off and the temperature of the reaction mixture was kept above 100 °C. After the addition was completed, the mixture was refluxed for an additional time (see below). The course of reaction was monitored by TLC and/ or NMR spectroscopy. After cooling to rt, the reaction mixture was poured into ice-water mixture (200 mL), acidified by the addition of acetic acid (5% solution in water), and extracted with ether (50 mL). The ethereal solution was washed with water, 5% Na2CO3, and again with water and dried over anhyd MgSO4. Evaporation of the solvent in vacuo gave crude acetal 18 or 19 which was purified by column chromatography (eluent, hexane:ether 4:1 for 18a,b,d,f, 19a,b, or 8:1 for 18e and 19c) or distilled (18c). Scale-up syntheses products can be easily purified by distillation. 1-Phenyl-1,3,3-triethoxypropane (18a): reaction time: 0.5 h; oil; yield 70% (based on the NMR);23 isolated yield 52%; bp 86-88 °C/2 Torr; 1H NMR δ 1.13-1.25 (m, 9H), 1.85-1.98 (m, 1H), 2.07-2.17 (m, 1H), 3.25-3.75 (m, 6H), 4.38 (dd, J ) 9.0 and 5.0 Hz, 1H). 4.64-4.66 (m, 1H), 7.25-7.40 (m, 5H); 13C NMR δ 15.1, 15.2, 15.3, 42.3, 61.0, 61.2, 63.8, 78.3, 100.2, 126.4 (2 C), 127.3, 128.2 (2 C), 142.4. Anal. Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.45; H, 9.36. 1-Phenyl-3,5,5-triethoxypent-1-yne (18b): reaction time: 2 h; oil; yield 85% (based on the NMR); isolated yield 33%; 1H NMR δ 1.20-1.28 (m, 9H), 2.03-2.12 (m, 1H), 2.20 (ddd, J ) 13.7, 8.2 and 5.5 Hz, 1H), 3.46-3.61 (m, 3H), 3.64-3.76 (m, 2H), 3.83-3.93 (m, 1H), 4.39 (dd, J ) 8.0 and 6.1 Hz, 1H), 4.80 (dd, J ) 6.1 and 5.8 Hz, 1H), 7.27-7.40 (m, 3H), 7.427.46 (m, 2H); 13C NMR δ 15.2, 15.4 (2 C), 40.2, 61.5, 61.7, 64.3, 66.6, 85.5, 88.2, 100.1, 122.8, 128.2 (3 C), 131.7 (2 C). Anal. Calcd for C17H24O3: C, 73.88; H, 8.75. Found: C, 73.85; H, 8.78. 1,1-Diethoxy-3-(2-methylpropoxy)butane(18c): reaction time: 0.5 h; oil; yield 72%; bp 61-63 °C/1.0-1.2 Torr; 1H NMR δ 0.90 (d, J ) 6.6 Hz, 3H), 0.91 (d, J ) 6.7 Hz, 3H), 1.13 (d, J ) 6.2 Hz, 3H), 1.20 (t, J ) 7.1 Hz, 3H), 1.21 (t, J ) 7.1 Hz, H), 1.68 (ddd, J ) 14.0, 7.6 and 4.3 Hz, 1H), 1.75-1.87 (m, 2H), 3.03 (dd, J ) 8.9 and 7.0 Hz, 1H), 3.30 (dd, J ) 9.0 and 6.3 Hz, 1H), 3.45-3.74 (m, 5 H), 4.69 (dd, J ) 7.6 and 4.0 Hz, 1H); 13C NMR δ 15.3, 15.4, 19.4, 19.5, 19.8, 28.8, 41.5, 61.0, 61.7, 72.1, 75.5, 100.7; HRMS calcd for C12H27O3 219.1960 [M+ + 1], found 219.1953. 1-Phenyl-3-(2-methylpropoxy)-5,5-diethoxypent-1yne (18d): reaction time: 6 h; oil; yield 85% (based on the NMR); isolated yield 37%; 1H NMR δ 0.94 (d, J ) 6.6 Hz, 3H), 0.96 (d, J ) 6.6 Hz, 3H), 1.23 (t, J ) 7.0 Hz, 3H), 1.24 (t, J ) 7.1 Hz, 3H), 1.87-1.96 (m, 1H), 2.05-2.14 (m, 1H), 2.21 (ddd, J ) 13.5, 8.5 and 5.2 Hz, 1H), 3.19 (dd, J ) 8.5 and 6.8 Hz, 1H), 3.50-3.62 (m, 3 H), 3.66-3.78 (m, 2 H), 4.37 (dd, J ) 8.2 and 5.8 Hz, 1H), 4.81 (dd, J ) 6.6 and 5.2 Hz, 1H), 7.29-7.33 (m, 3H), 7.41-7.46 (m, 2H); 13C NMR δ 15.3 (2 C), 19.4, 19.5, 28.5, 40.3, 61.5, 61.7, 66.9, 75.8, 85.4, 88.3, 100.1, 122.5, 128.2 (3 C), 131.7 (2 C). Anal. Calcd for C19H28O3: C, 74.96; H, 9.28. Found: C, 75.38; H, 9.42. 1-(Dodecyloxy)-1-phenyl-3,3-diethoxypropane(18e): reaction time: 1 h; oil; yield 70% (based on the NMR); isolated yield 29%; 1H NMR δ 0.89 (t, J ) 6.9 Hz, 3H), 1.15-1.40 (m, 22H), 1.50-1.62 (m, 2H), 1.89 (ddd, J ) 13.9, 7.4 and 4.8 Hz, 1H), 2.11 (ddd, J ) 13.7, 9.1 and 4.4 Hz, 1H), 3.18-3.25 (m, 1H), 3.27-3.37 (m, 1H), 3.45-3.75 (m, 6H), 4.35 (dd, J ) 9.1 and 4.7 Hz, 1H), 4.65 (dd, J ) 7.4 and 4.4 Hz, 1H), 7.20-7.50 (m, 5H); 13C NMR δ 14.0, 15.3 (2 C), 22.6, 26.2, 29.3, 29.4, 29.6 (3 C), 29.8, 31.8, 42.5, 60.9, 61.0, 61.4, 68.7, 78.6, 100.3, 126.4 (2 C), 127.3, 128.2 (2 C), 142.6; HRMS calcd for C25H45O3 393.3369 [M+ + 1], found 393.3347. (23) The “NMR yield” here and elsewhere indicates the percentage yield based on the desired product contained in the crude reaction mixture. This was calculated for compounds 13a-c, 16a,b, 22a,b as the proportion of the 1H NMR signal integrals of the protons in the R-position (to the benzotriazole moiety) of the intermediate to the corresponding byproduct. For compounds 18a,b,d-f, 19a-c a similar calculations were used for acetal group proton signals in the desired product and unreacted starting material.

Katritzky et al. 1,1-Diethoxy-3-(dodecyloxy)butane (18f): reaction time: 4 h; oil; yield 70% (based on the NMR); isolated yield 34%; 1H NMR δ 0.88 (t, J )7.0 Hz, 3H), 1.13-1.26 (m, 27H), 1.481.60 (m, 2H), 1.67 (ddd, J ) 13.9, 12.0 and 4.4 Hz, 1H), 1.82 (ddd, J ) 13.9, 8.9 and 4.0 Hz, 1H), 3.28 (dt, J ) 9.1 and 6.8 Hz, 1H), 3.47-3.55 (m, 4H), 3.58-3.72 (m, 2H), 4.67 (dd, J ) 7.5 and 3.4 Hz, 1H); 13C NMR δ 14.1, 15.4 (2 C), 19.9, 22.7, 26.3, 29.4, 29.5, 26.6 (4 C), 30.2, 31.9, 41.4, 61.0, 61.7, 68.6, 72.0, 100.8; HRMS calcd for C20H42O3 330.3134 [M+], found 330.3042. threo-2-Phenyl-3-(diethoxymethyl)tetrahydrofuran (19a): reaction time: 0.5 h; oil; yield 90% (based on the NMR); 1H NMR δ 1.13 (t, J ) 7.0 Hz, 3H), 1.21 (t, J ) 7.0 Hz, 3H), 1.91-2.16 (m, 2H), 2.49-2.58 (m, 1H), 3.42-3.58 (m, 3H), 3.60-3.75 (m, 1H), 3.91-3.98 (m, 1H), 4.04-4.12 (m, 1H), 4.51 (d, J ) 7.2 Hz, 1H), 4.82 (d, J ) 5.8 Hz, 1H), 7.21-7.40 (m, 5H); 13C NMR δ 15.0, 15.2, 28.2, 50.7, 61.4, 62.0, 68.0, 82.2, 103.7, 126.0 (2 C), 127.0, 128.1 (2 C), 143.1. This compound was characterized as its DNP derivative 20 (see below). threo-2-(1-Hexyn-1-yl)-3-(diethoxymethyl)tetrahydrofuran (19b): reaction time: 2.5 h; oil; yield 70% (based on the NMR); isolated yield 25%; 1H NMR δ 0.89-0.94 (m, 6H), 1.20-1.25 (m, 7H), 1.35-1.55 (m, 4H), 1.75-1.95 (m, 1H), 2.05-2.15 (m, 1H), 2.19-2.26 (m, 2H), 2.61 (ddd, J ) 13.2, 7.9 and 5.3 Hz, 1H), 3.40-3.60 (m, 1H), 3.62-3.78 (m, 1H), 3.82-3.98 (m, 2H), 4.38 (d, J ) 7.4 Hz, 1H), 4.49-4.51 (m, 1H); 13C NMR δ 13.4, 15.1 (2 C), 18.3, 21.8, 27.5, 30.5, 50.0, 61.2, 61.5, 67.1, 70.1, 79.3, 85.3, 103.0. Anal. Calcd for C15H26O3: C, 70.83; H, 10.30. Found: C, 70.83; H, 10.29. 2-Methyl-3-(diethoxymethyl)tetrahydropyran (19c): reaction time: 3 h; oil; yield 70% (based on the NMR); erythroisomer: yield 13% (after column chromatography, eluent: hexane:ether 8:1); 1H NMR δ 1.17-1.25 (m, 9H), 1.40-1.55 (m, 1H), 1.57-1.68 (m, 3H), 1.98-2.06 (m, 1H), 3.43-3.80 (m, 6H), 3.92 (ddd, J ) 13.5, 6.9 and 3.9 Hz, 1H), 4.42 (d, J ) 8.7 Hz, 1 H); 13C NMR δ 15.3, 15.4, 20.0, 22.3, 24.4, 41.0, 60.6, 61.2, 63.3, 71.7, 102.5; HRMS calcd for C11H23O3 203.1647 [M+ + 1], found 203.1651. Threo-isomer: yield 26% (after column chromatography, eluent: hexane:ether 8:1); 1H NMR δ 1.201.26 (m, 9H), 1.45-1.70 (m, 4H), 1.90-1.95 (m, 1H), 3.353.55 (m, 4H), 3.60-3.80 (m, 2H), 3.87-3.98 (m, 1H), 4.37 (d, J ) 3.0 Hz, 1H); 13C NMR δ NMR 15.1, 15.2, 19.9, 22.4, 25.8, 46.0, 63.3, 63.4, 67.6, 74.7, 103.8; HRMS calcd for C11H22O3 202.1569 [M+], found 202.1610. 2-Phenyl-1,2,3,4-tetrahydrofuran-3-carboxaldehyde 2,4Dinitrophenylhydrazone (20). Acetal 19a (0.50 g, 2 mmol) was dissolved in glacial acetic acid (15 mL), 2,4-dinitrophenylhydrazine (0.59 g, 3 mmol) was added, and the mixture was refluxed for 2 h. After cooling, the reaction mixture was dissolved in water, neutralized with 5% Na2CO3, and extracted with CHCl3 (2 × 20 mL). The combined organic extracts were washed with water, dried over anhyd MgSO4, and the solvent was evaporated in vacuo to give yellow solid which was recrystallized from EtOH to give dark yellow plates; yield 72%; mp 142-143 °C; 1H NMR δ 2.20-2.50 (m, 2H), 3.10-3.21 (m, 1H), 4.09-4.17 (m, 1H), 4.20-4.28 (m, 1H), 4.92 (d, J ) 7.5 Hz, 1H), 7.20-7.50 (m, 5H), 7.60 (d, J ) 5.8 Hz, 1H), 7.85 (d, J ) 9.5 Hz, 1H), 8.27 (dd, J ) 9.5 and 2.5 Hz, 1H), 9.07 (d, J ) 2.6 Hz, 1H), 11.08 (br s, 1H); 13C NMR δ 31.0, 50.7, 68.1, 83.5, 116.5, 123.3, 125.9 (2 C), 127.9, 128.6 (2 C), 129.1, 129.9, 138.1, 140.6, 144.4, 150.6. Anal. Calcd for C17H15N4O5: C, 15.77; H, 57.46; N, 4.25. Found: C, 15.70; H, 57.13; N, 4.52. General Procedure for the Preparation of N-MethylN-[1-(benzotriazolyl)-3,3-diethoxypropyl]acetamide(22a) and 1-[1-(Benzotriazolyl)-3,3-diethoxypropyl]pyrrolidin2-one (22b). A mixture of acetal 11 (1.00 g, 4.5 mmol), 1-vinyl2-pyrrolidinone or N-methyl-N-vinylacetamide (4.5 mmol), and BF3‚Et2O (0.03 mL) was stirred at 20 °C for 5 h. The reaction mixture was diluted with ether (50 mL) and subsequently washed with 1 M NaOH, brine, and water. Organic phase was separated and dried over anhyd MgSO4. Solvent was evaporated in vacuo to give colorless oil. N-Methyl-N-[1-(benzotriazolyl)-3,3-diethoxypropyl]acetamide (22a): oil; yield 90% (based on the NMR); 13C NMR δ 15.0, 16.6, 21.9, 30.0, 34.9, 61.2, 62.3, 99.5, 110.6, 119.4, 124.2, 127.7, 132.7, 145.5, 171.1.

Syntheses of β-Alkoxyalkanal and β-Aminoalkanal Acetals 1-[1-(Benzotriazolyl)-3,3-diethoxypropyl]pyrrolidin-2one (22b): oil isolated after synthesis solidified upon trituration with hexanes. White microcrystals; mp 79-81 °C; yield 70%; 1H NMR δ 1.11 (t, J ) 7.0 Hz, 3H), 1.19 (t, J ) 7.0 Hz, 3H), 1.78-1.95 (m, 1H), 1.95-2.11 (m, 1H), 2.28 (ddd, J ) 17.2, 9.6 and 6.4 Hz, 1H), 2.44 (ddd, J ) 17.2, 9.6 and 7.0 Hz, 1H), 2.68 (ddd, J ) 14.0, 6.9 and 6.9 Hz, 1H), 3.07 (ddd, J ) 14.0, 8.2 and 4.9 Hz, 1H), 3.20-3.37 (m, 2H), 3.45-3.71 (m, 4H), 4.38 (dd, J ) 6.6 and 4.9 Hz, 1H), 7.00 (dd, J ) 8.1 and 6.9 Hz, 1H), 7.35-7.43 (m, 1H), 7.52 (t, J ) 8.0 Hz, 1H), 7.837.89 (m, 1H), 8.02-8.07 (m, 1H); 13C NMR δ 15.0, 15.1, 17.6, 30.6, 34.9, 42.3, 60.2, 61.4, 62.4, 99.3, 110.4, 119.3, 124.2, 127.7, 132.6, 145.4, 174.9. Anal. Calcd for C17H24N4O3: C, 61.43; H, 7.28; N, 16.86. Found: C, 61.64; H, 7.22; N, 17.48. General Procedure for the Preparation of the AminoAcetals (24a,b). To a stirred under nitrogen solution of the corresponding acetal 22a,b (10 mmol) in dry THF (100 mL) was added NaAlH4 (1.08 g, 20 mmol) in one portion. (CAUTION! A strong evolution of heat is observed; use external cooling). The reaction mixture was stirred at rt for 1 h, and 20% NaOH was then added portionwise. A mixture was stirred for 20 min and extracted with ether (3 × 50 mL). The combined extracts were washed twice with 5% NaOH and then with water and dried over anhyd MgSO4. The solvent was evaporated in vacuo to yellow-orange oil. The crude product was subjected to flash column chromatography (ethyl acetate) and then to distillation. N-[1-(3,3-Diethoxypropyl)]-N-ethylmethylamine (24a): oil; yield 82%; bp 42-45 °C/4 Torr; 1H NMR δ 1.09 (t, J ) 7.1 Hz, 3H), 1.22 (t, J ) 7.1 Hz, 6H), 1.80-1.87 (m, 2H), 2.26 (s, 3H), 2.44-2.51 (m, 4H), 3.47-3.57 (m, 2H), 3.62-3.72 (m, 2H), 4.58 (t, J ) 5.5 Hz, 1H); 13C NMR δ 12.0, 15.0, 31.2, 41.3, 51.1, 52.3, 60.7, 101.4; HRMS calcd for C10H24NO2 190.1807 [M++ 1], found 190.1809.

J. Org. Chem., Vol. 62, No. 3, 1997 705 N-[1-(3,3-Diethoxypropyl)]pyrrolidine (24b): oil; yield 92%; bp 65-68 °C/1 Torr; 1H NMR δ 1.21 (t, J )7.1 Hz, 6H), 1.76-1.82 (m, 4H), 1.83-1.90 (m, 2H), 2.45-2.55 (m, 6H), 3.46-3.56 (m, 2H), 3.61-3.71 (m, 2H), 4.59 (t, J ) 5.6 Hz, 1H); 13C NMR δ 15.3, 23.4, 33.1, 51.8, 54.2, 60.9, 101.6; HRMS calcd for C11H24NO2 202.1807 [M+ + 1], found 202.1812. Reaction of Acetal 24b with Phenylmagnesium Bromide. To a stirred solution of the acetal 24b (0.61 g, 3 mmol) in toluene (50 mL) was added a solution of phenylmagnesium bromide (9 mmol) in ether (6 mL) dropwise at reflux under nitrogen. The course of the reaction was monitored by NMR. After 5 h the reaction mixture was cooled to rt and poured into water (200 mL), extracted with ether (2 × 50 mL), and successively washed with brine and water. Organic phase was separated and dried over anhyd MgSO4. The solvent was evaporated in vacuo to give the oily residue. Column chromatography (ethyl acetate/MeOH, 9:1) afforded N-[1-(3-ethoxy3-phenylpropyl)]pyrrolidine (25); oil; yield 60%; 1H NMR δ 1.17 (t, J ) 7.0 Hz, 3H), 1.73-1.90 (m, 5H), 1.99-2.11 (m, 1H), 2.39-2.56 (m, 6H), 3.26-3.43 (m, 2H), 4.31 (dd, J ) 7.4 and 6.0 Hz, 1H), 7.23-7.36 (m, 5H); 13C NMR δ 15.2, 23.4, 37.6, 52.8, 54.1, 63.9, 80.4, 126.4 (2 C), 127.2, 128.2 (2 C), 142.9; HRMS calcd for C15H24NO 234.1858 [M+ + 1], found 234.1857.

Supporting Information Available: 1H and 13C NMR spectra for compounds 18c, 18e, 18f, 19c, 24a, 24b, 25 (14 pages). This material is contained in libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information. JO9612335